WENTWORTH, 21 May 2015 (AFP) - Molinari carded a seven-under par 65 with no bogeys finishing with a flourish with birdies at the 17th and 18th –- both par-5s -– to leave himself two shots in front of Sweden's Robert Karlsson and six in front of McIlroy who had a 71.
Karlsson is a shot in front of a clutch of players on four-under including 2008 winner Miguel Angel Jimenez, another Spaniard in Jorge Campillo, England's Chris Wood and Korea's YE Yang.
Denmark's Thomas Bjorn shot a 69 whilst Luke Donald, triumphant in 2012 and 2013, had a steady 70 to keep himself in the hunt.
Molinari hinted at a return to form with a tie for second place at the Spanish Open last week but he tumbled out of the world top-50 last October and currently stands 66th in the rankings.
The 32-year-old needs a good finish to boost his chances of playing in the US Open in June, where the top-60 in the world on Monday get exemptions and July's British Open at St Andrews where the top-50 are granted automatic spots.
"I know that the deadline for the U.S. Open and The Open are close and it would mean a lot to have a good week here," Molinari told reporters. "All season, I've been pretty much just outside the Top‑50, knowing that a good week would get me in again.
"Dropping out of the Top‑50 didn't help because it means I need to play more events. I missed the Masters this year and a few majors in a row. So it wasn't a nice feeling, and I hope to be back very soon."
McIlroy fresh from his win at Quail Hollow in the United States last week had started with a bogey at the par-4 first and was never better than one-under par and could not manage a birdie on the two closing par-5s.
"I felt like I left a couple out there.There's definitely room for improvement," said McIlroy.
McIlroy is following a relentless schedule flying into London from the United States on Monday, attending the European Tour's Players' Awards dinner on Tuesday night and is playing his fourth of five tournaments in as many weeks.
And the Northern Irishman was aiming to put his feet up after venting his frustrations on the course during his first round.
"Mentally I feel myself getting a bit angry out there which I haven't been doing the last few weeks," he said.
"I just sort of need to stay in control of my emotions because I feel like that's one of the things, if I'm a little tired or a little fatigued mentally, I'll start to be hard on myself and start to get down on myself. I will try not to do that over the next few days."
Molinari's brother Edoardo retired with a wrist injury after playing 16 holes in eight –over par and three-time major winner Padraig Harrington of Ireland lasted two holes before walking off with shoulder trouble.
Leading and selected scores from the first round of the European PGA Championship at Wentworth on Thursday (par 72):
65 – Francesco Molinari (ITA)
67 – Robert Karlsson (SWE)
68 – Jorge Campillo (ESP), Miguel Angel Jimenez (ESP), Chris Wood (ENG), YE Yang (KOR), Marc Warren (SCO)
69 - Tommy Fleetwood (ENG), Pablo Larrazabal (ESP), Nicolas Colsaerts (BEL), Peter Lawrie (IRL), Thomas Bjorn (DEN), Jerome Lando Casanova (FRA)
70 – Felipe Aguilar (CHI), Jamie Donaldson (WAL), Thongchai Jaidee (THA), Ian Ellis (ENG), Gregory Havret (FRA), Shiv Kapur (IND), Luke Donald (ENG), Alexander Levy (FRA), Damien McGrane (IRL)
71 – Rory McIlroy (NIR), Andy Sullivan (ENG), Victor Dubuisson (FRA), Ignacio Garrido (ESP), Byeong Hun An (KOR), Emiliano Grillo (ARG), James Morrison (ENG), Richie Ramsay (SCO), Justin Rose (ENG), Danny Willett (ENG), Prom Meesawat (THA), Soren Hansen (DEN), Soren Kjeldsen (DEN), Bradley Dredge (WAL), Jason Palmer (ENG)
Selected:
72 – Ernie Els (RSA), Anirban Lahiri (IND), Martin Kaymer (GER), Lee Westwood (ENG), Brett Rumford (AUS), Jeev Milkha Singh (IND)
73 – SSP Chawrasia (IND), Marcus Fraser (AUS), Wade Ormsby (AUS)
74 – Simon Khan (ENG), Darren Clarke (NIR), Graeme McDowell (NIR), Shane Lowry (IRE)
75 – Matteo Manassero (ITA)
76 – Peter Uihlein (USA)
79 – Paul Lawrie (SCO)
85 – Jin Jeong (KOR)
Withdrew:
Padraig Harrington (IRL), Edoardo Molinari (ITA)